Complications from atherosclerosis represent a major cause of morbidity and mortality in Western society. The accumulation of low-density lipoprotein (LDL)-derived cholesterol and inflammatory cells in the artery wall are the initiating events that cause atherosclerosis. However, the factors that underlie the initiation of atherosclerosis are still poorly understood. Our recent data suggest that one such factor may be caveolin-1 (Cav-1), an important structural component of caveolae. Caveolae are 50-100 nm flask-shaped invaginations of plasma membrane, and Cav-1 is essential for caveolae biogenesis in several tissues, including the arterial endothelium. Physiologically, the loss of caveolae results in impairment of cholesterol homeostasis, insulin resistance, nitric oxide production (NO), and defects in cardiopulmonary and vascular function. Interestingly, mice deficient in Cav-1 exhibit resistance to atherosclerosis despite a marked proatherogenic lipid profile, suggesting that Cav-1 determines the athero-susceptibility to the vessel wall. We recently demonstrated the critical role of endothelial Cav-1 during the progression of atherosclerosis in mice. Mice were generated lacking Cav-1 and ApoE but expressing endothelial-specific Cav-1 in the double knockout background (ApoE-/-Cav-1REC). Genetic ablation of Cav-1 on the ApoE knockout background inhibited the progression of atherosclerosis, while re-expression of Cav-1 in the endothelium promoted lesion expansion. Several different mechanism appear to be involved, including reduced LDL infiltration into the artery wall, increased production of nitric oxide (NO), reduced expression of leukocyte adhesion molecules and decreased monocyte accumulation in atherosclerotic plaques. The precise mechanisms by which Cav-1 and/or caveolae controls all of these events remains unknown. Thus, a major challenge of this grant proposal is to determine the molecular mechanism by which endothelial-specific Cav-1 controls the early stages and progression of atherosclerosis. We propose three aims. Aim 1: To investigate the molecular mechanism by which Cav-1 regulates lipoprotein trafficking in the artery wall and lipid/lipoprotein metabolism in arterial endothelial cells. Aim 2: To define the role of NO in the atheroprotection observed in Cav-1 null mice. Aim 3: To define whether Cav-1 expression regulates EC inflammatory response and macrophage mobilization in vivo. In summary completion of these aims will provide insight into fundamental regulatory mechanism by which Cav-1/caveolae regulates lipoprotein metabolism and the progression of atherosclerosis.